Fluticasone furoate

Identification

Name

Fluticasone furoate

Accession Number

DB08906

Type

Small Molecule

Groups

Approved

Description

Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. Despite the similarity in the names, fluticasone furoate and fluticasone propionate are different drugs with different properties. It is marketed under the brand name, Veramyst in the US by GlaxoSmithKline for the management of chronic obstructive pulmonary disease (COPD). FDA approved on April 27, 2007.

Fluticasone furoate is available as a combination product with vilanterol, a long-acting beta-2 agonist, under the tradename Breo Ellipta. Approved by the FDA in 2013, its use is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. It is also indicated for once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease.

Pharmacology

Indication

Fluticasone furoate nasal spray is indicated for the treatment of the symptoms of seasonal and perennial allergic rhinitis in patients aged 2 years and older.

Breo Ellipta, a mixture of fluticasone furoate and vilanterol is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. It is also indicated for once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease. Breo Ellipta should not be used for the relief of acute symptoms of asthma or COPD.

Fluticasone furoate binds to human glucocorticoid receptor more potently than dexamethasone (29.9-times) and fluticasone propionate (1.7-times). It also is highly retained in respiratory tissue. The significance of this finding is that fluticasone furoate may have a more pronounced and prolonged anti-inflammatory effect, which allows for once-daily dosing. It does not have any effect on the QTc interval. Furthermore, fluticasone furoate was not found to affect the hypothalamic-pituitary-adrenal axis function in adolescent and adult asthma.

Mechanism of action

Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. Fluticasone is also found to increase airway retention of long-acting beta adrenergic agonist, thus potentiating its beneficial effects for the treatment of asthma.

Following intranasal administration of fluticasone furoate, most of the dose is eventually swallowed and undergoes incomplete absorption and extensive first-pass metabolism in the liver and gut, resulting in negligible systemic exposure. Even at the highest recommended intranasal dose of 110 mcg once daily, plasma concentrations were not quantifiable. This is an especially useful feature as it lowers the incidence of adverse events associated with corticosteroid use. If administered using oral solution and intravenous dosing, 30% of the drug is absorbed and rapidly cleared from the plasma.
Absolute bioavailability, intranasal route = 0.5%;
Absolute bioavailability, oral route = 1.26%;
Mean lung absorption time = 7 hours (regardless of formulation);

Volume of distribution

Steady state, IV administration = 608 L

Protein binding

>99% protein bound.

Metabolism

Fluticasone furoate does not undergo cleavage into its two separate components, fluticasone and the furoate moiety. It undergoes extensive hepatic metabolism via CYP3A4. The principal route of metabolism is hydrolysis of the S-fluoromethyl carbothioate function to form the inactive 17β-carboxylic acid metabolite. Studies suggest that enterocytes may be involved in the metabolism of unabsorbed drug.

Route of elimination

Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered dose, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered dose, respectively. Fluticasone furoate is extensively metabolized so very little is excreted unchanged.